Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no effective therapy for RSV. Synagis (palivizumab), a monoclonal antibody (mAb) that binds RSV, is given by intramuscular injection to a small subset of high-risk infants as immunoprophylaxis. However, it is not effective at treating RSV, and both pediatric and geriatric RSV patients are simply placed on supportive therapy. We believe a pathogen-specific, safe, effective and topically delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Human mAb delivered locally to mucosal surfaces offer exceptional promise combining safety, effectiveness and unparalleled specificity. Adding further to the promise of mAb, the Lai Lab recently discovered a novel antibody function in mucus ? trapping individual pathogens in mucus ? and have pioneered a technology enhancing the use of mAb in mucosal secretions based on carefully-tuned affinity between IgG-Fc and mucins, which has been exclusively licensed to Mucommune. We have shown that engineered mAb can trap a variety of pathogens in different human mucus secretions at sub-neutralizing concentrations. In turn, this prevents pathogens from accessing the underlying epithelium, facilitates rapid elimination, and enables effective protection in vivo, underscoring the broad applicability of the Mucommune technology. Interestingly, RSV sheds exclusively from the apical surface of infected cells, indicating that RSV must traverse airway mucus (AM) before spreading to neighboring cells. Therefore, we seek to harness our mAb technology and develop a ?muco-trapping? variant of the palivizumab mAb that can be delivered directly to the airways by nebulization, thereby reducing the spread of RSV in the lung and facilitating rapid elimination of the virus. We will build upon pilot studies that demonstrate mAb can potently trap RSV in human AM, facilitate rapid elimination of viral particles from the mouse lung airways, and remain stable when nebulized using a vibrating mesh nebulizer. In Aim 1, working together with Tony Hickey at RTI, we will verify that nebulization of mAb for delivery into the small airways will maintain the structural stability and native antigen-binding affinity of the mAb, and estimate the dose that can be delivered to the pediatric lung. In Aim 2, we will validate that nebulized ?muco-trapping? palivizumab can retain its muco-trapping function in fresh human AM, and effectively reduce RSV titers when delivered via nebulization to cotton rats following RSV challenge. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on developing a shelf-stable formulation that could be nebulized and administered to pediatric patients with diagnosed RSV infection. By enabling enhanced mAb function in mucus secretions, we expect Mucommune will help pave the way for improved, molecularly-targeted therapies and prophylaxis against a broad spectrum of pathogens and microbes across all major mucosal surfaces.